{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T17:48:25Z","timestamp":1782841705486,"version":"3.54.5"},"reference-count":40,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Institution for Trials"},{"name":"SWOG Hope Foundation"},{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Trastuzumab deruxtecan (T-DXd) has transformed the treatment paradigm for HER2-expressing breast cancer, including HER2-low disease. However, biomarkers associated with T-DXd activity remain poorly defined. We conducted a comprehensive analysis of clinical, genomic, and immune correlates of T-DXd outcomes to identify molecular determinants of therapeutic benefit and resistance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We retrospectively analyzed 2 independent cohorts of patients with advanced breast cancer treated with T-DXd at Dana-Farber Cancer Institute and Yale Cancer Center between 2018 and 2024. We included patients with \u22652 tumor blocks with HER2 immunohistochemistry (IHC) assessments prior to T-DXd. Clinical data on 524 patients were manually reviewed, and genomic profiling and immune microenvironment assessments were performed on a subset of patients. Multivariable Cox proportional hazards models evaluated associations between molecular features and overall survival (OS) and time to next treatment (TTNT).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 524 patients, HER2 IHC discordance between sequential tumor biopsies was observed in 20% of patients and was independently associated with significantly worse OS (hazard ratio [HR]\u2009=\u20090.67; P\u2009=\u2009.012) and TTNT (HR\u2009=\u20090.65; P\u2009=\u2009.002), resembling outcomes seen in HER2 0 tumors. Genomic analysis revealed that PTEN mutations correlated with inferior TTNT (HR\u2009=\u20092.2; q\u2009=\u20090.068), whereas ERBB2 amplifications predicted improved OS and TTNT. An inflamed tumor microenvironment determined by digital pathology was associated with significantly poorer TTNT outcomes (median TTNT = 5.5\u2009months) compared with immune-desert phenotypes (median OS = 9.6\u2009months, P\u2009=\u2009.03).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study identifies HER2 IHC discordance and specific genomic and immune features as prognostic biomarkers of T-DXd efficacy. These findings warrant prospective validation and may inform biomarker-driven strategies to optimize T-DXd therapy in HER2-expressing malignancies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jnci\/djaf344","type":"journal-article","created":{"date-parts":[[2025,11,25]],"date-time":"2025-11-25T13:00:06Z","timestamp":1764075606000},"page":"669-679","source":"Crossref","is-referenced-by-count":1,"title":["Molecular and clinical insights of trastuzumab deruxtecan efficacy in advanced breast cancer"],"prefix":"10.1093","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8084-9105","authenticated-orcid":false,"given":"Amin H","family":"Nassar","sequence":"first","affiliation":[{"name":"Division of Medical Oncology, Yale Cancer Center , New Haven, CT,","place":["United States"]},{"name":"Division of Pulmonary Medicine, Brigham and Women\u2019s Hospital , Boston, MA,","place":["United 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